Endometriosis is a gynaecologic disease characterized by ectopic implantation of endometrial cells outside the uterus, causing pelvic pain and infertility. Ectopic endometrial cells show increased proliferation and migration capability. Somatostatin (SRIF, somatotropin release inhibitory factor) and its analogues have been shown to inhibit normal and cancer cell proliferation and motility, via a family of G-protein coupled receptors (GPCRs) termed sst1-5. Cortistatin (CST), which shows high structural and functional homology with SRIF, binds all ssts and also MrgX2, a GPCR not bound by SRIF. Our first purpose was to investigate gene expression of SRIF, CST, and their receptors in ectopic endometrial tissues of endometriosis patients, in primary endometrial cells (ESCs) isolated from these tissues and in the human endometrial cell line T HESCs. Secondly, we tested the hypothesis that SRIF, its analogues and CST would inhibit platelet-derived growth factor (PDGF)-induced proliferation and motility in T HESCs. Gene expression was evaluated by real-time PCR in ectopic endometrial tissues, ESCs and T HESCs. T HESC motility was determined by wound healing assay and beta-actin rearrangement; cell proliferation by Alamar blue assay. ERK1/2 and Akt phosphorylation was assessed by Western Blot. We found that ectopic endometrial tissues and primary ESCs expressed SRIF, CST, all ssts and MrgX2 mRNA. The T HESC cell line showed SRIF, CST, sst1, sst2 and sst3, but not sst4, sst5 and Mrgx2 mRNA. SRIF, its synthetic analogue SOM230 and CST counteracted PDGF-induced proliferation and motility in T HESC endometrial cells. They also reduced basal and PDGF-induced ERK1/2 phosphorylation. Finally, SRIF reduced VEGF, MMP-2, PDGF-Ra and PDGF-Rb gene expression, and, in the presence of PDGF, promoted sst1 and sst2 expression. In conclusion, we report that SRIF, CST and their receptors are expressed in ectopic endometrial tissues and cells from endometriosis patients. Moreover SRIF, CST and their analogues inhibit PDGF-induced proliferation and motility in the endometrial cell line T HESC. These data could potentially be relevant for understanding the pathogenesis of endometriosis and for designing new therapeutic strategies.
SOMATOSTATIN, SOMATOSTATIN ANALOGUES AND CORTISTATIN REDUCE PDGF-INDUCED ENDOMETRIAL CELL PROLIFERATION AND MOTILITY
ANNUNZIATA, Marta;GRANDE, CRISTINA;GHIGO, Ezio;GRANATA, Riccarda
2009-01-01
Abstract
Endometriosis is a gynaecologic disease characterized by ectopic implantation of endometrial cells outside the uterus, causing pelvic pain and infertility. Ectopic endometrial cells show increased proliferation and migration capability. Somatostatin (SRIF, somatotropin release inhibitory factor) and its analogues have been shown to inhibit normal and cancer cell proliferation and motility, via a family of G-protein coupled receptors (GPCRs) termed sst1-5. Cortistatin (CST), which shows high structural and functional homology with SRIF, binds all ssts and also MrgX2, a GPCR not bound by SRIF. Our first purpose was to investigate gene expression of SRIF, CST, and their receptors in ectopic endometrial tissues of endometriosis patients, in primary endometrial cells (ESCs) isolated from these tissues and in the human endometrial cell line T HESCs. Secondly, we tested the hypothesis that SRIF, its analogues and CST would inhibit platelet-derived growth factor (PDGF)-induced proliferation and motility in T HESCs. Gene expression was evaluated by real-time PCR in ectopic endometrial tissues, ESCs and T HESCs. T HESC motility was determined by wound healing assay and beta-actin rearrangement; cell proliferation by Alamar blue assay. ERK1/2 and Akt phosphorylation was assessed by Western Blot. We found that ectopic endometrial tissues and primary ESCs expressed SRIF, CST, all ssts and MrgX2 mRNA. The T HESC cell line showed SRIF, CST, sst1, sst2 and sst3, but not sst4, sst5 and Mrgx2 mRNA. SRIF, its synthetic analogue SOM230 and CST counteracted PDGF-induced proliferation and motility in T HESC endometrial cells. They also reduced basal and PDGF-induced ERK1/2 phosphorylation. Finally, SRIF reduced VEGF, MMP-2, PDGF-Ra and PDGF-Rb gene expression, and, in the presence of PDGF, promoted sst1 and sst2 expression. In conclusion, we report that SRIF, CST and their receptors are expressed in ectopic endometrial tissues and cells from endometriosis patients. Moreover SRIF, CST and their analogues inhibit PDGF-induced proliferation and motility in the endometrial cell line T HESC. These data could potentially be relevant for understanding the pathogenesis of endometriosis and for designing new therapeutic strategies.
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